Follicular lymphoma (FL) constitutes the second most common B-cell Non-Hodgkin's lymphoma (B-NHL) with an annual incidence of ~14,000 cases and more than 100,000 patients in the US living with the disease. Despite improvements in the survival of FL patients, the disease remains incurable and patients go through cycles of treatment, remission and relapse. Targeted or risk-adapted FL therapies are not available or are substantially less active than in either chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL). Consequently, the societal health burden of FL is high. The majority of FL is characterized by the recurrent translocation t(14;18) resulting in increased expression of Bcl2 but this is neither sufficient nor necessary for FL development. Recently, novel inroads into the genomic pathogenesis of FL have been made and have resulted in a description of recurrent structural genomic alterations as well as recurrent gene mutations in FL. However, existing data are incomplete and comparatively little is known about functional or mechanistic consequences of these genomic aberrations. Importantly, FL still receives comparatively little scientific attention, and as a consequence, FL pathogenesis remains largely obscure. This reflects, at least in part that few centers have developed the translational infrastructure to study primary FLs and that accurate experimental tools to study FL have been lacking and all available cell lines are derived from transformed FLs. Over the last 7 years, we have developed the infrastructure to prospectively collect and analyze FLs and to correlate novel molecular findings with clinical characteristics and outcome and have undertaken genomic and functional approaches to dissect the pathogenesis of FL. In parallel, we have developed a genetically and pathologically accurate murine model of FL that enables rapid analysis of potential disease-driving mutant alleles. We have combined our complementary expertise to establish a program of functional genetic studies focused on FL. Our initial genomic studies, which will be expanded as part of this application, have yielded a rich source of novel candidate genomic FL drivers and these will now be tested for functional implications. We have reported that 27% of FL carry mutations in the linker histone H1 family of genes (HIST1H1-B-E) and that these mutations are largely mutually exclusive with mutations in EZH2 and ARID1A. We hypothesize that these mutations promote FL development through perturbation of either shared and/or alternate epigenetic pathways. Our exciting discovery of activating FL-associated STAT6 mutations forms the basis for detailed mechanistic studies as outlined in Aim 3. Overall, we will define how recurrently altered genes drive FL lymphomagenesis and will explore therapeutic opportunities resulting from these novel insights.